Efficacy Of Acetylcholinesterase Inhibitors Research Articles

Efficacy of Acetylcholinesterase Inhibitors in the Logopenic Variant of Primary Progressive Aphasia

Introduction: For over 25 years, cholinesterase inhibitors (ChEIs) have been the main symptomatic treatment for Alzheimer’s disease (AD). Several meta-analyses have supported their effectiveness in various neurocognitive, functional, and behavioral aspects of amnestic AD. Over 86% of cases of the logopenic variant of primary progressive aphasia (lvPPA), also named language variant AD, are caused by a similar pathologic process than AD, yet no study has examined the efficacy of ChEIs in this AD variant. We aimed to explore the efficacy of ChEIs in the treatment of lvPPA by comparing their evolution on the MMSE, and other functional and behavioral parameters, to that of treated amnestic AD patients. Methods: A retrospective chart review was performed in 45 patients with lvPPA and 52 patients with amnestic AD. Both groups were similar in terms of age, level of education, and onset of symptoms. Drug history and MMSE scores, as well as functional (activities of daily living [ADLs] and instrumental activities of daily living [IADLs]), neurocognitive and neuropsychiatric symptoms were collected on several time points before and after the introduction of ChEIs. Data were analyzed using ANOVA and a generalized linear mixed model. Results: Patients with lvPPA showed a similar trajectory of decline than amnestic AD patients on serial MMSEs up to 12–24 months after the introduction of ChEIs. There was a significant impact on ADLs but not IADLs and neuropsychiatric symptoms remained stable over time. Conclusion: This study provides preliminary evidence for efficacy of ChEIs in patients with lvPPA and suggests similar benefits to those seen in amnestic AD patients, hence reassuring patients and their physicians.

Efficacy of Acetylcholinesterase Inhibitors on Cognitive Function in Alzheimer's Disease. Review of Reviews.

Alzheimer’s disease (AD) is the most common form of dementia over the age of 65. It is estimated that 115.4 million people will be affected by AD by 2050. Acetylcholinesterase inhibitors (AChEI) are the only available and approved treatment for AD. The aim of the present study was to analyse the evidence on the efficacy of the AChEI in the treatment of cognitive symptoms of Alzheimer’s disease. For that purpose, a review of review of the systematic reviews (SRs) on this topic was carried out by Web of Science, PubMed, and The Cochrane Library, among others, were searched until 24 September 2021. Thirteen of the 1773 articles evaluated the efficacy of AChEI on cognitive function and/or general condition and/or behavioural disturbances of patients with mild to moderate AD. Methodological quality and risk of bias were rated using the ROBIS scale. The quality of the identified studies was high for nine of them, unclear for two, and finally only in two of the 13 studies did we detect low quality. Overall, AChEI showed very low efficacy in improving cognition in patients with mild to moderate AD. Better results were obtained in improving global state, with donepezil being the most effective treatment. No improvements in behavioural disturbances were found. Few high-quality reviews provide clear evidence of the effects of AChEI on cognition, global change, behaviour, and mortality. The data suggest that AChEI stabilize or slow cognitive deterioration, improving global status. In addition, data indicate that the use of AChEI decreases mortality in patients with mild to moderate AD. However, there is no evidence that they improve patient behaviour. Donepezil is the best therapeutic alternative at a dose of 10 mg/day.

Acupuncture therapy for Alzheimer's disease: The effectiveness and potential mechanisms.

Alzheimer's disease (AD) is a common neurodegenerative disease that accounts for approximately 70% of dementia. Following the global escalation of the aging process, the morbidity of AD is increasing rapidly. The current treatment for AD is mainly limited to medications, such as acetylcholinesterase inhibitors. However, the efficacy of acetylcholinesterase inhibitors in improving memory and cognitive functions is not satisfactory. It is a challenge to find an effective alternative therapy for ameliorating AD symptoms. As an important therapeutic technique in traditional Chinese medicine, acupuncture has been proved effective in treating many neurologic diseases including AD. The efficacy of acupuncture is also acknowledged by the National Institutes of Health of the United States. Here, we summarized the effectiveness of acupuncture for treating AD. Especially, the role of acupuncture at certain acupuncture points in modulating the brain function through meridians activity based on Chinese meridian theory is discussed. How acupuncture at a certain acupoint can improve AD symptoms is also described. Furthermore, the possible molecular mechanisms of acupuncture for AD are reviewed, and the role of acupuncture in modulating signaling molecules in neural protection and homeostasis is highlighted. This study may help to understand the theoretical basis and potential molecular mechanisms of acupuncture therapy for AD.

Farmakologiczne leczenie choroby Alzheimera — współczesne możliwości

Approximately 46 million people worldwide have Alzheimer’s disease (AD). Treatments to prevent or slow down cognitive decline in AD remain an urgent therapeutic need. During the last decades the use of b secretase inhibitors as well as immunotherapy against Ab, antioxidants and anti-inflammatory agents as well as natural products and many others have been investigated. Although considerable efforts have been made to develop more effective therapeutic agents for AD therapy, clinical trials failed to reach efficacy endpoints in improving cognitive function in most cases to date or have been terminated due to adverse events. Current pharmacotherapy of AD is still limited to cholinesterase inhibitors and the N-methyl-D-aspartate antagonist memantine which were approved at the turn of the century. Despite critical opinions on the efficacy of acetylcholinesterase inhibitors and memantine, it should be said that these drugs improve memory and other cognitive functions throughout most of the duration of the disease. As Memantine, and the AChEIs target two different aspects of AD pathology their complementary mechanisms offer superior benefit as combination therapy. Moreover preclinical studies have shown that memantine and AChEIs have neuroprotective effects.

Rivastigmine patch reduces the incidence of postoperative delirium in older patients with cognitive impairment.

To date, data regarding the efficacy of acetylcholinesterase inhibitors in preventing postoperative delirium (POD) are inconsistent and conflicting. Older individuals with cognitive dysfunction are thought to show POD more frequently. Our aim was to study the effectiveness of rivastigmine prophylaxis on the incidence, severity, and risk factors for POD in older patients with cognitive impairment undergoing hip fracture surgery. Of 62 older patients with cognitive impairment about to undergo surgery after a hip fracture, 31 were randomly assigned to receive a rivastigmine patch from 3 days before to 7 days after the operation (Group I), and the other 31 did not receive a rivastigmine patch (Group II). The two groups were compared with regard to incidence and severity of delirium on postoperative days 2 or 3 and 7. Multivariate logistic regression analysis was performed to assess factors associated with POD. Postoperative delirium occurred in five Group I patients and 14 Group II patients (p = 0.013). The mean severity of delirium in the two groups as determined by the Delirium Rating Scale was 2.2 and 6.2 respectively (p = 0.033). The odds ratio for POD was 0.259 (95% CI: 0.074-0.905, p = 0.034) after adjusting for American Society of Anesthesiologists score (p = 0.058), age (p = 0.203), and gender (p = 0.560). There were no rivastigmine-related perioperative complications. Perioperative rivastigmine patch application could reduce the occurrence of POD in older patients with low cognitive status. Copyright © 2016 John Wiley & Sons, Ltd.

Determination of affinity and efficacy of acetylcholinesterase inhibitors using isothermal titration calorimetry

BackgroundAcetylcholinesterase (AChE), an enzyme rapidly terminating nerve signals at synapses of cholinergic neurons is an important drug target in treatment of Alzheimer's disease and related memory loss conditions. Here we present comprehensive use of isothermal titration calorimetry (ITC) for investigation of AChE kinetics and AChE-inhibitor interactions. MethodsAcetylcholinesterase (AChE, EC 3.1.1.7) from Electrophorus electricus was assayed for interactions with five well known AChE inhibitors, galanthamine, tacrine, donepezil, edrophonium and ambenonium. In ITC experiments the inhibitors were injected to the enzyme solution solely (for thermodynamic characterization of binding) or in presence of the substrate, acetylcholine (for determination of inhibitors potency). ResultsDetailed description of various experimental protocols is presented, allowing evaluation of inhibitors potency (in terms of IC50 and Ki) and thermodynamic parameters of the binding. The potency of tested inhibitors was in nano to micromolar range which corresponded to activities determined in conventional method. Binding of all inhibitors showed to be enthalpy driven and obtained Ka values demonstrated good correlation with the data from standard Ellman's assay. ConclusionsObtained results confirmed the usability of the ITC technique for comprehensive characterization of AChE-inhibitor interactions and AChE kinetics. The method reduced the complexity of reaction mixture and interference problems with the advantage of using natural substrates. General significanceThe work reports complete thermodynamic characteristics of the AChE — inhibitor complexes. Due to the universal character of ITC measurements, described protocols can be easily adapted to other enzymatic systems. This article is part of a Special Issue entitled Microcalorimetry in the BioSciences — Principles and Applications, edited by Fadi Bou-Abdallah.

Acetylcholinesterase inhibitor modifications: a promising strategy to delay the progression of Alzheimer's disease.

Alzheimer's disease (AD), a fatal, progressive, neurodegenerative disorder, is the most common cause of old-age dementia, accounting for 50–75% of dementia patients. Early stages of AD are marked by vocabulary shrinkage, spatial disorientation, depression, apraxia, and deterioration of recent forms of declarative memory. In course of time, the patients require close supervision due to the loss of cognitive and functional abilities, and at the terminal stages of the disease, all forms of memory are severely impaired with the patients needing nursing home care (World Alzheimer Report, 2013).

Donepezil-Induced Confusional State in a Patient With Autopsy-Proven Behavioral-Variant Frontotemporal Dementia

Donepezil-Induced Confusional State in a Patient With Autopsy-Proven Behavioral-Variant Frontotemporal Dementia

Effect of foxo1 polymorphism on efficacy of acetylcholinesterase inhibitors in older patients with Alzheimer's disease

Effect of foxo1 polymorphism on efficacy of acetylcholinesterase inhibitors in older patients with Alzheimer's disease

Cholinesterase inhibitor use is associated with increased plasma levels of anti-Abeta 1–42 antibodies in Alzheimer's disease patients

Acetyl-cholinesterase inhibitors (AChEI) are drugs frequently prescribed for the treatment of Alzheimer's disease (AD), exerting an effect on cognition, as well as on behavioural and psychological symptoms of dementia and activities of daily living. The efficacy of AChEI may be ascribed not only to the activation of cholinergic transmission, but also to other mechanisms, among which a putative regulation of the immune response has already been hypothesized. In the present study, we evaluated, in a cross-sectional sample of 66 AD patients and 48 healthy controls, the putative influence of AChEI on anti-Abeta 1–42 antibody plasma levels by ELISA assay. AD patients receiving AChEI therapy showed increased plasma levels of anti-Abeta 1–42 antibodies respect to untreated AD patients and antibodies levels similar to those of healthy controls, both before and after normalization by total IgG values. Our results support a potential role of AChEI in the modulation of the immune response against Abeta. We suggest that a strategy aimed at increasing the endogenous response against this peptide might represent an interesting therapeutic target to be further investigated.

Best Practice Guide for the Treatment of REM Sleep Behavior Disorder (RBD)

Modifying the sleep environment is recommended for the treatment of patients with RBD who have sleep-related injury. Level A Clonazepam is suggested for the treatment of RBD but should be used with caution in patients with dementia, gait disorders, or concomitant OSA. Its use should be monitored carefully over time as RBD appears to be a precursor to neurodegenerative disorders with dementia in some patients. Level B Clonazepam is suggested to decrease the occurrence of sleep-related injury caused by RBD in patients for whom pharmacologic therapy is deemed necessary. It should be used in caution in patients with dementia, gait disorders, or concomitant OSA, and its use should be monitored carefully over time. Level B Melatonin is suggested for the treatment of RBD with the advantage that there are few side effects. Level B Pramipexole may be considered to treat RBD, but efficacy studies have shown contradictory results. There is little evidence to support the use of paroxetine or L-DOPA to treat RBD, and some studies have suggested that these drugs may actually induce or exacerbate RBD. There are limited data regarding the efficacy of acetylcholinesterase inhibitors, but they may be considered to treat RBD in patients with a concomitant synucleinopathy. Level C.

Effects of Donepezil, Galantamine and Rivastigmine in 938 Italian Patients with Alzheimerʼs Disease

Acetylcholinesterase inhibitors (AChEIs) have been used to improve cognitive status and disability in patients with mild to moderate Alzheimer's disease (AD). However, while the efficacy of AChEIs (i.e. how they act in randomized controlled trials) in this setting is widely accepted, their effectiveness (i.e. how they behave in the real world) remains controversial. To compare the effects of three AChEIs, donepezil (Aricept), galantamine (Reminyl) and rivastigmine (Exelon), in an Italian national, prospective, observational study representative of the 'real world' clinical practice of AChEI treatment for AD. 938 patients with mild to moderate AD collected within the framework of the Italian National Cronos Project (CP), involving several UVAs (AD Evaluation Units) spread over the entire national territory, who were receiving donepezil, galantamine or rivastigmine were followed for 36 weeks by measuring: (i) function, as determined by the Activities of Daily Living (ADL) and Instrumental Activities of Daily Living (IADL) scales; (ii) cognition, as measured by the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) [primary outcome measures]; and (iii) behaviour, as measured on the Neuropsychiatric Inventory (NPI) and Clinical Dementia Rating (CDR) scale. Moreover, all patients were genotyped for apolipoprotein E (apoE) genetic variants. No statistically significant improvement in the primary outcome measures (MMSE and ADAS-Cog) was observed with drug therapy at 36 weeks, at which point all groups had lost, on average, 1 point on the MMSE and gained 2-3 points on the ADAS-Cog scale compared with baseline. On the secondary outcome measures at week 36, all treatment groups showed a significant worsening on the ADL and IADL scales compared with baseline, while on the NPI scale there were no significant differences from baseline except for the galantamine-treated group which worsened significantly. Moreover, patients receiving galantamine worsened significantly compared with the donepezil-treated group on the IADL scale. ApoE epsilon4 allele did not influence the effect of drug therapy. Over a 36-week follow-up period, no significant difference in the effects of donepezil, galantamine and rivastigmine on a variety of functional and cognitive parameters was observed in a large number of apoE-genotyped patients with mild to moderate AD recruited within the framework of a national project representative of the scenario usually encountered in actual clinical practice in Italy. The limitations (possibility of administration of lower drug doses than are used in clinical trials, relatively short follow-up period and the lack of randomization) and strengths (large number of patients, concomitant observation of the three drugs and the number of parameters assessed, including apoE genotype) of the present study are acknowledged. Our type of naturalistic study should complement clinical trials because 'real world' practice operates in the face of the numerous variables (e.g. health status and co-morbidities) associated with a complex disease such as AD in elderly people.

Acetylcholinesterase inhibitors for Alzheimer’s disease: anti-inflammatories in acetylcholine clothing!

The pathogenesis of Alzheimer's disease (AD) has been linked to a deficiency in the brain neurotransmitter acetylcholine. Subsequently, acetylcholinesterase inhibitors (AChEIs) were introduced for the symptomatic treatment of AD. The prevailing view has been that the efficacy of AChEIs is attained through their augmentation of acetylcholine-medicated neuron to neuron transmission. However, AChEIs also protect cells from free radical toxicity and beta-amyloid-induced injury, and increased production of antioxidants. In addition, it has been reported that AChEIs directly inhibit the release of cytokines from microglia and monocytes. These observations are supported by evidence showing a role for acetylcholine in suppression of cytokine release through a 'cholinergic anti-inflammatory pathway'. Based on the accumulating research data so far, it is no longer appropriate to consider that the sole action of AChEIs in AD is through direct acetylcholine-medicated enhancement of neuronal transmission. Evidence points to a possible anti-inflammatory role for these agents as well.

Progress in acetylcholinesterase inhibitors for Alzheimer’s disease

Current pharmacotherapy of Alzheimer’s disease (AD) involves drugs that are known as acetylcholinesterase inhibitors (AChEIs), which increase the acetylcholine concentration in the brain. Although effective in improving cognitive, behavioural and functional impairments, these drugs are not able to alter disease progression. In this review, the recent patent literature on AChEIs from 2002 to early 2005 will be discussed, focusing attention on the novel analogues of the approved drugs, as well as on the most important AD therapeutic advances. The clinical efficacy of AChEIs will probably be enhanced by their combination with other drugs acting through different pharmacological mechanisms. As the neuronal loss comprises more than the forebrain cholinergic system, the weak effectiveness of AChEIs is not surprising. Besides the ‘cholinergic hypothesis’ approaches, new treatments are emerging based on multipotent compounds able to target the underlying pathogenic mechanisms of AD; these treatments are summarised herein.

Vascular dementia

The past decade has seen a renewed interest in vascular dementia. The search for a causal relationship between a vascular event or a vascular cerebral lesion and dementia has led to new classification schemes which no longer consider vascular dementia a homogeneous entity but acknowledge the diversity of the clinical and morphological substrates of this syndrome. Deviation from the term "multi-infarct dementia" is only one but many consequencies of these recent developments. Etiologically, vascular dementia may result from cerebral small vessel disease leading to extensive leucencephalopathy or lacunes or may be the consequence of strategically located infarcts or multiple infarcts in large vessel territories. It may also be the consequence of global cerebral hypoperfusion, intracerebral hemorrhage or other mechanisms such as vasculitis. There is no definitive medical or surgical treatment for vascular dementia. Thus, it appears that stroke prevention offers the most immediate and substantial solution to reduce the morbidity and mortality. This is best substantiated for treatment of arterial hypertension. Once vascular dementia occurs control of vascular risk factors may be useful but this contention will require larger scale studies to provide more definite proof. A number of metabolically active drugs has been used for the treatment of cognitive symptoms in vascular dementia. Yet, the data are conflicting und the effects described modest at most. There is epidemiological evidence for a more than incidental co-existence between vascular and primary degenerative dementia which suggests that therapies found to be effective in Alzheimer's disease may also prove beneficial at least in subgroups of vascular dementia. Lately, this concept is tested by several studies on the efficacy of acetylcholinesterase inhibitors in vascular dementia.

Examining the modest efficacy of acetylcholinesterase inhibitors in AD

Examining the modest efficacy of acetylcholinesterase inhibitors in AD